Neuropharmacology. 2025 Aug 9:110632. doi: 10.1016/j.neuropharm.2025.110632. Online ahead of print.
ABSTRACT
BACKGROUND: Previous studies have demonstrated that ketamine’s metabolic conversion to (2S, 6S; 2R, 6R)-HNK is indispensable for its fast-onset and long-lasting antidepressant-like actions, and moreover, both (2R, 6R)-HNK and (2S, 6S)-HNK exert N-methyl-D-aspartate receptor (NMDAR)-independent antidepressant-like activities. Up to date, many pharmacological targets other than NMDAR have been reported for (2R, 6R)-HNK and (2S, 6S)-HNK. We have previously found that salt-inducible kinase 1 (SIK1) and cAMP response element binding protein (CREB)-regulated transcription co-activator 1 (CRTC1) in the paraventricular nucleus (PVN) participate in depression neurobiology by regulating the hypothalamic-pituitary-adrenal (HPA) axis, and here, we assume that (2R, 6R)-HNK and (2S, 6S)-HNK may also produce effects on the two molecules.
METHODS: Male C57BL/6 mice, chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS), behavioral tests, enzyme linked immunosorbent assay (ELISA), western blotting, co-immunoprecipitation (Co-IP), quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence, and adeno-associated virus (AAV)-mediated gene knockdown were adopted.
RESULTS: Administration of (2R, 6R)-HNK/(2S, 6S)-HNK fully reversed both CUMS-induced and CSDS-induced depressive-like behaviors, HPA hyperactivity, and dysfunction in the SIK1-CRTC1 system in the PVN of mice. AAV-mediated genetic knock-down of SIK1 in PVN neurons significantly abolished the reversal effects of (2R, 6R)-HNK and (2S, 6S)-HNK against CUMS and CSDS.
CONCLUSIONS: SIK1 and CRTC1 in PVN neurons participate in the antidepressant-like mechanism of (2R, 6R)-HNK and (2S, 6S)-HNK, extending the knowledge of their pharmacological targets.
PMID:40789506 | DOI:10.1016/j.neuropharm.2025.110632
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